Thesis (Ph.D. (Pharmacy))--North-West University, Potchefstroom Campus, 2008.

Graduation date: 1993

Thesis (M.Sc.)--Memorial University of Newfoundland, School of Pharmacy, 1997. / Typescript. Bibliography: leaves 116-141.

Thesis (Ph. D.)--School of Biomedical Engineering, Georgia Institute of Technology, 2004. Directed by Mark R. Prausnitz. / Includes bibliographical references (leaves 184-193).

Thesis (M.S.)--West Virginia University, 2003. / Title from document title page. Document formatted into pages; contains vii, 70 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 69-70).

Acyclovir is an antiviral drug used in the treatment and prevention of herpes simplex and varicella-zoster viral infections. The major problem in the transdermal delivery of acyclovir is the permeation in sufficient amounts to deeper layers of the skin and into the systemic circulation. Acyclovir is a hydrophilic substance with a low partition coefficient, resulting in poor penetration through the excellent barrier of the skin, the stratum corneum. In an attempt to enhance the transdermal permeability of acyclovir, the aim of this study was to employ terpenes as possible penetration enhancers. Terpenes are constituents of natural essential oils, with widespread medicinal use including in aromatherapy. The terpenes used in this study were 1,8-cineole, limonene, menthol, menthone, and 13- myrcene. Terpenes are not only used as penetration enhancers, but are even more often present in drugs and cosmetics. Limited studies have been done concerning the penetration of terpenes through the skin. Thus, not only the effect of the terpenes on the penetration of acyclovir, but also the penetration of the terpenes themselves were studied. The influence of acyclovir on the penetration of the terpenes was also determined. In vitro permeation experiments were performed on human skin using Franz diffusion cells. The skin was pretreated with a 5 % solution of the terpene in ethanol and left for 30 minutes to enable ethanol evaporation and terpene incorporation into the skin. Saturated aqueous solutions of acyclovir (pH 7.4) were added in the donor compartment before and after skin pre-treatment. The acyclovir concentration retrieved from the receptor compartment of the Franz cells was analyzed by HPLC. The amount of terpene that penetrated were semi-quantitatively determined by GC. Penetration of acyclovir was significantly enhanced by two terpenes, viz. 1,8-cineole and menthol. The extent of enhancement was, however, not large enough to be of clinical use. The enhancement in acyclovir penetration observed upon ethanol pre-treatment alone, or in the presence of limonene, menthone or ~-myrcene, was not significant. Penetration enhancement of acyclovir by the terpenes was in accordance with previous studies, which postulated better enhancement of hydrophilic drugs by hydrophilic terpenes. Large percentages of the terpenes with log P values within the optimum log P range (1 - 3) penetrated, as was found with menthone and menthol. Penetration decreased accordingly as the log P, and thus lipophilicity, increased. Stratum corneum retention is regarded as the most plausible explanation for this phenomenon. In the case of 1,8- cineole, enhancer pooling in the stratum corneum could be a possible reason for its poor penetration. Acyclovir significantly influenced the penetration profiles of some of the terpenes, but no clear explanation could be given. / Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.

The skin forms an attractive and accessible route for systemic delivery of drugs as alternative to other methods of administration, such as the oral and parental methods because of the problems associated with last mentioned methods. The lipophilic character of the stratum corneum, coupled with its intrinsic tortuosity, ensures that it almost always provides the principal barrier to the entry of drug molecules into the skin. Due to the fact that methotrexate (MTX) and acyclovir (ACV) have poor penetration properties through the skin, the aim of this study was to enhance the permeation of methotrexate and acyclovir with the use of two lamellar gel phase systems (LPGS) (Physiogel® NT and Physiogel® Dermaquadrille) and with Emzaloid® as transdermal drug delivery systems. Three different sets of experiments were done in this study: 1) the viscosity of the two Physiogel® creams was measured as an indication of stability and to determine whether the internal structure of the Physiogel® creams were affected by the investigated drugs; 2) the drug release rate from the three drug delivery vehicles was measured with a Vankel ® dissolution apparatus; 3) in vitro permeation studies were preformed using vertical Franz diffusion cells with human epidermal skin clamped between the donor and receptor compartments. The skin was hydrated with PBS buffer for one hour before 1% mixtures of the drugs in both the Physiogel® creams and Emzaloid® were applied to the donor chamber. Samples were taken at 2, 4, 6, 8, 10, 12 and 24 hours. It was then analysed by HPLC for methotrexate and acyclovir. The fluxes of drug permeation were determined. The viscosity measurements confirmed that the internal structure of the two Physiogel® creams was not influenced by the drugs. Acyclovir and methotrexate were both released from the delivery vehicles. There was an enhancement of acyclovir through the skin from one of the Physiogel® creams. The permeability of methotrexate in the presence of the two Physiogel® vehicles was not significantly enhanced. Emzaloid® as delivery vehicle increased the penetration of both drugs through the skin significantly. The lamellar gel phase system mimics the structure of the stratum corneum, but does not improve the drug permeation through the stratum corneum significantly. The utilisation of Emzaloid® as a drug delivery system could be advocated from these findings. As could be seen from the penetration profiles Emzaloid® was a superior delivery system for methotrexate and acyclovir compared to the lamellar gel phase systems. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.

The skin is the largest and most easily accessible organ of the human body thus making it the ideal route for systemic drug delivery. The transdermal route of drug delivery offers several advantages compared to the traditional routes including elimination of first pass metabolism and higher patient compliance. However, many drugs are topically and systemically ineffective when applied onto the skin, due to their almost complete failure to penetrate the skin. The main limitation lies in the stratum corneum, the barrier of the skin, which prevent the drug from reaching the deeper skin strata. 5-Fluorouracil is a polar hydrophilic drug and is therefore not a good penetrant through skin. A popular technique to increase transdermal permeation is to use a penetration enhancer, which reversibly reduce the permeability barrier of the stratum corneum. The primary aim of this study was to determine the effect of Brij 97 in the presence and absence of carrageenan on the transdermal delivery of 5-fluorouracil. The formulations were identified by means of confocal laser scanning microscopy and measurement of the particle size. The zeta-potential was measured to determine whether the formulations were stable and the pH was measured to determine if the internal structures of the formulations were affected by the drug. The drug released from the formulations was measured with a VanKel dissolution apparatus. In vitro transdermal diffusion studies were performed using vertical Franz diffusion cells with human epidermal skin. Histopathological studies were carried out on human epidermis skin to determine if the surfactant, Brij 97, had any effect on the skin. Through confocal laser scanning microscopy and particle size measurements, the 4 and 8% Brij 97 formulations without carrageenan could be identified as emulsions while the 15 and 25% Brij 97 formulations without carrageenan could be identified as microemulsions. The 4, 8, 15 and 25% Brij 97 formulations containing carrageenan could be identified as gels. The results obtained from the zeta-potential analysis indicated that the 4 and 8% Brij 97 formulations without carrageenan and 4% Brij 97 formulation with carrageenan are the most electronegative and thus the most stable. The pH measurements confirmed that the internal structure of the formulations was not influenced by the drug. 5-Fluorouracil was released from the formulations. The 4 and 8% Brij 97 formulations without carrageenan had an enhancing effect on the penetration of 5-fluorouracil while the 4, 8, 15 and 25% Brij 97 formulations with carrageenan and the 15 and 25% Brij 97 formulations without carrageenan had an hindering effect on the penetration of 5-fluorouracil. Although carrageenan led to good adhesiveness of the formulation on the skin, it did not lead to the enhancement of the penetration of 5-fluorouracil through the skin. When histopathological studies were carried out on female human abdominal skin, Brij 97, the surfactant, was found to have no damaging effect on the skin structure. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2006.

This thesis aimed to investigate and document the potential of applying ceramics in two specific drug delivery applications: tamper-resistant opioid formulations and transdermal enhancement protrusions. Geopolymers were developed into the matrix for a tamper-resistant formulation, aiming to protect drug substances from non-medical abuse. The synthesis conditions and excipients composition of the geopolymer-based formulation were modified in this work to facilitate a stable and extended drug delivery. Results showed that 37ºC 100% humidity for 48 hours were applicable conditions to obtain geopolymer with suitable mechanical strength and porosity. Moreover, it was found that the integration of poly(methyl acrylate) into the geopolymer-based formulation could reduce the drug release at low pH and, meanwhile, maintain the mechanical strength. Therefore, the geopolymer-based drug formulations concluded from these studies were applied in oral and transdermal delivery systems. Evidence of the tamper-resistance of geopolymer-based oral and transdermal formulations was documented and compared to the corresponding commercial opioid formulations. The results provided experimental support for the positive effects of geopolymers as drug carriers for the tamper-resistance of oral and transdermal delivery systems. Self-setting bioceramics, calcium phosphate and calcium sulfate were fabricated into transdermal enhancement protrusions in this work for the first time. Results showed that, under mild conditions, both bioceramics could form pyramid-shaped needles in the micron size. The drug release from these needles could be controlled by the bulk surface area, porosity and degradation of the bioceramics. An in vitro insertion test showed that the bioceramic microneedles had enough mechanical strength to insert into skin. Further optimization on the geometry of needles and the substrate material was also performed. The higher aspect-ratio needles with a flexible and self-swellable substrate could release most of the drug content within 4 hours and could penetrate through the stratum corneum by manual insertion. This study explored the potential application of bioceramics in transdermal enhancement protrusions and showed promising indication of their future developments.

Acyclovir is an antiviral drug used in the treatment and prevention of herpes simplex and varicella-zoster viral infections. The major problem in the transdermal delivery of acyclovir is the permeation in sufficient amounts to deeper layers of the skin and into the systemic circulation. Acyclovir is a hydrophilic substance with a low partition coefficient, resulting in poor penetration through the excellent barrier of the skin, the stratum corneum. In an attempt to enhance the transdermal permeability of acyclovir, the aim of this study was to employ terpenes as possible penetration enhancers. Terpenes are constituents of natural essential oils, with widespread medicinal use including in aromatherapy. The terpenes used in this study were 1,8-cineole, limonene, menthol, menthone, and 13- myrcene. Terpenes are not only used as penetration enhancers, but are even more often present in drugs and cosmetics. Limited studies have been done concerning the penetration of terpenes through the skin. Thus, not only the effect of the terpenes on the penetration of acyclovir, but also the penetration of the terpenes themselves were studied. The influence of acyclovir on the penetration of the terpenes was also determined. In vitro permeation experiments were performed on human skin using Franz diffusion cells. The skin was pretreated with a 5 % solution of the terpene in ethanol and left for 30 minutes to enable ethanol evaporation and terpene incorporation into the skin. Saturated aqueous solutions of acyclovir (pH 7.4) were added in the donor compartment before and after skin pre-treatment. The acyclovir concentration retrieved from the receptor compartment of the Franz cells was analyzed by HPLC. The amount of terpene that penetrated were semi-quantitatively determined by GC. Penetration of acyclovir was significantly enhanced by two terpenes, viz. 1,8-cineole and menthol. The extent of enhancement was, however, not large enough to be of clinical use. The enhancement in acyclovir penetration observed upon ethanol pre-treatment alone, or in the presence of limonene, menthone or ~-myrcene, was not significant. Penetration enhancement of acyclovir by the terpenes was in accordance with previous studies, which postulated better enhancement of hydrophilic drugs by hydrophilic terpenes. Large percentages of the terpenes with log P values within the optimum log P range (1 - 3) penetrated, as was found with menthone and menthol. Penetration decreased accordingly as the log P, and thus lipophilicity, increased. Stratum corneum retention is regarded as the most plausible explanation for this phenomenon. In the case of 1,8- cineole, enhancer pooling in the stratum corneum could be a possible reason for its poor penetration. Acyclovir significantly influenced the penetration profiles of some of the terpenes, but no clear explanation could be given. / Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.